Parkinson's Disease
Coördinators: Henk Berendse and Peter Heutink
Clinical Approach:
Clinical testing, magnetoencephalography (MEG), and structural and functional magnetic resonance imaging (MRI) are used to study the pathophysiology of non-motor symptoms in PD, including cognitive impairment and dementia, emotional symptoms, and olfactory deficits. The functional imaging studies using MEG and MRI focus on the role of changes in (the pattern of) resting state and task-related synchronization of activity within and between distributed brain areas. Repetitive transcranial magnetic stimulation (rTMS) is used as a tool to selectively modulate activity in functional brain networks and thus further increase our understanding of the changes in cortico-cortical and cortico-striatal communication in PD.
Efforts to develop early diagnostic markers for PD include clinical studies of the diagnostic value of early stage non-motor symptoms, in particular olfactory dysfunction, as well as nuclear imaging studies using positron emission tomography (PET) and single photon emission computed tomography (SPECT). The latter studies are aimed at developing radioligands that enable the visualization of central aspects of the disease process, such as protein accumulation, and/or the monitoring of disease progression and the effects of alleged neuroprotective agents.
In addition we perform histopathological studies on post-mortem human brain tissue. These studies are aimed at tracking the pattern of progression of disease-specific pathological changes (alpha-synuclein and tau proteins) in extranigral brain areas, including early stage, pre-symptomatic PD patients. In addition, genomics and proteomics are applied to post-mortem human brain tissue to find stage-specific gene and protein expression profiles, respectively. In parallel to the neuropathological studies, protein expression are studied in cerebrospinal fluid and serum samples of well-characterized cohorts of PD patients. Proteomics and biochemical analyses are combined to discover proteins that are associated with disease progression and/or specific clinical phenotypes, and hence may serve as biomarkers for PD.
Neurogenetic studies
Our neurogenetic studies are aimed at genes involved in common forms of PD, FTD (Frontotemporal Dementia) and AD (Alzheimer's Disease). In collaboration with the LUMC/AMC and UMCN a large cohort of PD patients is currently available for genetic studies (~800 patients). The goal is to increase this cohort in the coming years to at least 2000 cases. Agreements with the UMCN have been made for an addition 700 cases. Also at the VUmc, a cohort will be collected. For FTD a cohort of more then 500 cases is available in collaboration with the ErasmusMC. For AD and other forms of dementia the cohort consists of over 1500 samples. Although, several biological pathways have been put forward for common neurodegenerative disorders no systematic genotypic has been performed for these pathways. In the currently available cohort we now systematically analyse these pathways for their role in disease. When we reach the stage where we have ascertained appropriate numbers of cases for genome wide association studies these studies will be initiated. In addition to patients from the general population we have collected PD patients from several genetically isolated populations which have been used for the identification of a new locus for idiopathic PD for which we currently perform studies to identify the biologically functional variants.
We also continue our work on monogenic forms of neurodegenerative diseases. In collaboration with the departments of neurology and clinical genetics families with Mendelian forms of disease are identified and ascertained and we receive families from other centers as well. Localisation studies using a linkage based approach are routinely performed and we identified new loci for which positional cloning efforts are currently underway. Other studies are aimed at determining the prevalence of known AD/PD-related genes and to identify unexplained familial cases. As common forms of neurodegenerative disease have a strong relation with general aging one can expect similar pathways and mechanisms to be involved in healthy aging. Within the EMGO research institute a large longitudinal aging cohort (LASA) has been collected that was recently made available for genetic studies. This cohort can be used as a control cohort for our patient studies but in addition, identified genes can be tested for their role in ageing.
Proteomics-Biomarking
We have developed a novel quantitative proteomics platform to dissect the molecular basis of initiation and expression of PD and AD. We will examine protein expression and posttranslational modifications of synaptosome, mitochondria, and protein aggregates in relevant brain regions from mouse models and human post-mortem tissue for neurodegenerative disease The proteomes of organelles and CSF will be analysed using iTRAQ tagging and LC/LC-MS/MS. The peptides will be subjected to multi-dimensional liquid chromatography in conjunction with tandem mass spectrometry. The fragment ions of peptide backbone reveal peptide identity; the peak areas of iTRAQ signature ions will be used for peptide quantitation. Posttranslational modifications including phosphorylation and ubiquitination will be detected, based on the characteristic fragmentation patterns of the posttranslational modification. Using an integrated proteomics analysis of a matrix of brain tissues of mutants, pharmacological animal models, and selective pull-down of protein complexes, we will reveal proteins at the intersection of pathways that may be involved in the induction and expression of neurodegeneration.
